- Epilepsy
- Multiple Sclerosis
- Parkinson's disease
- Migraine
- Tourette’s syndrome
Epilepsy
- Epilepsy affects approximately 50 million people worldwide. The prevalence of this disease is estimated to be between 4 and 10 per 1000 people.
- The use of cannabis and particularly cannabidiol (CBD) in the treatment of epilepsy has become widespread based on pre-clinical and clinical research findings, as well as on multiple anecdotal evidence of significant improvements in various types of difficult-to-control, unclassified epilepsy and in the context of syndromes such as Dravet and Lennox-Gastaut.
- The most compelling clinical trials have been conducted with purified CBD. It is important to note that this is a coadjuvant treatment, in which other antiepileptic drugs are not suspended. Furthermore, it is a third line treatment when the patient has not improved despite receiving two or more appropriate antiepileptic drugs in maximum tolerated doses (this is known as Refractory Epilepsy).
- In patients receiving CBD for Refractory Epilepsy, in addition to the reduction of seizures by more than 50%, an impact on emotional, cognitive and motor function has also been observed, which is reflected in improved socialization and quality of life.
CLINICAL EVIDENCE
Cannabidiol in patients with seizures asso with LGS (GWPCARE4) a randomised double-blind, placebo controlled phase 3 trial The Lancet 2018 (391) 1085
CBD as an adjuvant is effective in the treatment of patients with atonic seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being evaluated in the open-label extension of this trial.
CCBD-enriched medical cannabis for intractable pediatric epilepsy The current Israeli experience Seizure 2016 (35) 41-44
The results of this multicentre study on cannabidiol treatment for intractable epilepsy in a population of children and adolescents are very promising. Prospective, well-designed clinical trials using cannabidiol-enriched medical cannabis are justified
Epilepsy & Behav 29 (2013) 574-577
Safety and tolerability data for the use of cannabidiol-enriched cannabis among children are not available. Objective measurements of a standardised preparation of pure cannabidiol are needed to determine whether it is safe, well-tolerated and effective in controlling seizures in this difficult-to-treat pediatric population.
Lancet Neurol 15 (2016) 270-78 Cannabidiol in patients with treatment-resistant epilepsy an open-label interventional trial
The findings suggest that cannabidiol may reduce the frequency of seizures and may have an adequate safety profile in children and young adults with treatment-resistant epilepsy.
NEJM 376(21) (2017) 2011-20 Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome
Among patients with Dravet syndrome, cannabidiol at a dose of 20 mg/kg/day resulted in a greater reduction in seizure frequency compared to placebo and was associated with a higher rate of adverse events.
Multiple Sclerosis
- Clinical studies have shown that medical cannabis may improve some of the symptoms that accompany Multiple Sclerosis, including spasticity, painful muscle spasms and cramps. Some clinical trials suggest a decrease in centrally induced pain, and in frequency of urination.
CLINICAL EVIDENCE
Yadav, V., Bever, C., Bowen, J. Bowling, A., Weinstock-Guttman, B., Cameron, M., ... & Narayanaswami, P. (2014). Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology, 82(12), 1083-1092.
Oral extracts of medicinal cannabis have been shown to be effective in the management of spasticity and pain associated with multiple sclerosis and are recommended as part of the management of these symptoms in the American Academy of Neurology's guide to complementary therapies.
Rice, J., & Cameron, M. (2018). Cannabinoids for treatment of MS symptoms: state of the evidence. Current neurology and neuroscience reports, 18(8), 50.
In addition to studies for pain and spasticity with a significant number of patients evaluated, cases of improvement in urinary urgency have been reported anecdotally. However, more studies are needed to confirm this finding.
Fragoso, Y. D., Carra, A., & Macias, M. A. (2020). Cannabis and Multiple Sclerosis. Expert Review of Neurotherapeutics.
Among the wide range of symptoms that can be seen in multiple sclerosis is spasticity. This phenomenon consists of an involuntary increase in muscle tone. Some studies have shown significant improvement in this symptom with the use of medical cannabis.
Parkinson's disease
Parkinson disease’s (PD) is the fastest growing neurological disorder in the world, and it is estimated that about 10 million people worldwide are living with PD.
- Research with CBD has shown that these cannabinoid could help manage the symptoms of Parkinson's disease.
CBD is a potent antioxidant that can protect neurons from damage caused by oxidative stress (very relevant in Parkinson's disease).
- Studies in humans have shown a positive impact of CBD on the quality of life, hallucinations, and REM sleep disorder in patients with PD.
CLINICAL EVIDENCE
Chagas, Marcos Hortes N., et al. "Effects of cannabidiol (CBD) in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial." Journal of Psychopharmacology 28.11 (2014): 1088-1098.
The group of patients to whom CBD was administered showed significant improvement in quality of life, with activities of daily living, emotional well-being and mobility being the domains of greatest impact.
Chagas, M. H., Eckeli, A. L., Zuardi, A. W., Pena‐Pereira, M. A., Sobreira‐Neto, M. A., Sobreira, E. T., ... & Tumas, V. (2014). Cannabidiol (CBD) can improve complex sleep‐related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: a case series. Journal of clinical pharmacy and therapeutics, 39(5), 564-566.
The administration of CBD was associated with dramatic improvement in the symptoms of REM sleep disorder in patients with Parkinson's disease.
Migraine
- A growing body of evidence points to a possible role of the endocannabinoid system in the management of episodic and chronic migraines, as well as headaches due to the abuse of analgesics. Activation of CB1 receptors with THC, anandamide or nabilone seems to be beneficial for this condition.
CLINICAL EVIDENCE
Rhyne, D. N., Anderson, S. L., Gedde, M., & Borgelt, L. M. (2016). Effects of medical marijuana on migraine headache frequency in an adult population. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 36(5), 505-510.
Retrospective study of medical records review. We included 121 patients diagnosed with migraine who used medical cannabis in various presentations for migraine crisis management and headache prophylaxis. Follow-up at 21 months on average. The primary outcome was the number of migraine episodes per month. There was a statistically significant decrease from 10.4 to 4.6 monthly episodes. Medical cannabis may be useful in the treatment of migraine.
Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial
Prospective, double-blind, randomized study evaluating the use of Nabilone (synthetic cannabinoid) versus ibuprofen for analgesia-abuse headache in 30 patients A statistically significant decrease in headache intensity was documented. The reduction was 17% with ibuprofen and 30% with cannabinoid. A reduction in analgesic consumption was achieved in 57.7% of the nabilone group.
Tourette’s syndrome
- Evidence supporting the efficacy of cannabis is limited, although clinical data arising from case reports, controlled trials and observational studies indicates that THC-rich cannabis and cannabis-based medicines may improve tics, comorbidities and health-related quality of life in adults with Tourette’s syndrome.
- Therefore, after exhausting psychological and behavioral intervention and licensed medications, medical cannabis containing THC may be helpful. However, there is still limited evidence to support the administration of THC-rich cannabis to patients under the age of 18 due to a higher risk of developing neurobehavioral comorbidities, especially when associated to other risk factors such as a family history of schizophrenia or concomitant use of alcohol and tobacco.
CLINICAL EVIDENCE
Müller-Vahl, K. R. Treatment of Tourette
syndrome with cannabinoids. Behav. Neurol. 27,
119–24 (2013).
Clinical review of anecdotal reports and two controlled trials available investigating the effect of THC in the treatment of TS. Using both self and examiner rating scales, in both studies a significant tic reduction could be observed after treatment with THC compared to placebo, without causing significant adverse effects. Available data about the effect ofTHC on obsessive-compulsive symptoms are inconsistent. According to a recent Cochrane review on the efficacy of cannabinoids in TS, definite conclusions cannot be drawn, because longer trials including a larger number of patients are missing. Notwithstanding this appraisal, by many experts THC is recommended for the treatment of TS in adult patients, when first line treatments failed to improve the tics. In treatment resistant adult patients, therefore, treatment with THC should be taken into consideration.
Milosev, L. M., Psathakis, N., Szejko, N.,
Jakubovski, E. & Müller-Vahl, K. R. Treatmentof Gilles de la Tourette Syndrome with Cannabis-Based Medicine: Results from a Retrospective Analysis and Online Survey.
A retrospective data analysis including adult patients who had used CBM for the treatment of GTS at some time. All patients were asked to complete an online survey (second study part) to receive more detailed data about treatment with CBM. From these results, it is further supported that CBM might be effective and safe in the treatment of tics and comorbidities at least in a subgroup of adult patients with GTS. In our sample, patients favored THC-rich cannabis over dronabinol and nabiximols, which might be related to the entourage effect of cannabis. However, several limitations of the study must be taken into considerations such as the open uncontrolled design and the retrospective data analysis
- Schizophrenia
- Anxiety Disorder
- Behavioural symptoms of dementia
- Post-Traumatic Stress Disorder
- Insomnia
Schizophrenia
- The use of phytocannabinoids in schizophrenia is restricted exclusively to CBD. This cannabinoid has been shown to have antipsychotic effects by regulating the endocannabinoid system and not by dopamine antagonism. CBD doses for schizophrenia are usually relatively high (e.g. 1000 mg/day) and should always be accompanied by the antipsychotics the patient is taking. At no time is it intended to replace conventional antipsychotics, let alone be given in monotherapy. For this reason, CBD may be indicated in cases of refractoriness.
- CBD is generally very well tolerated in this population and its motor; metabolic and endocrine adverse effects are very low compared to conventional treatments for schizophrenia. An additional advantage, revealed in several studies, is the possible therapeutic effect on the negative symptoms of schizophrenia. Finally, it should be remarked that the use of THC is contraindicated in schizophrenia.
CLINICAL EVIDENCE
Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. American Journal of Psychiatry. 2017. Philip McGuire, F.R.C.Psych., F.Med.Sci., Philip Robson, M.R.C.P., F.R.C.Psych., Wieslaw Jerzy Cubala, M.D., Ph.D., Daniel Vasile, M.D., Ph.D., Paul Dugald Morrison, Ph.D., M.R.C.Psych., Rachel Barron, B.Vet.Med., M.R.C.V.S., Adam Taylor, Ph.D., Stephen Wright, F.R.C.P.(Edin), F.F.P.M.
In an exploratory double-blind parallel-group trial, patients with schizophrenia were randomised at a 1:1 ratio to receive cannabidiol (CBD) along with their existing antipsychotic medication. Participants were assessed before and after treatment using the Positive and Negative Symptom Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), the Global Assessment of Functioning Scale (GAF) and the Clinical Global Impression Improvement and Severity Scales (CGI-I and CGI-S).
After 6 weeks of treatment, the CBD group had lower levels of psychotic symptoms. Patients receiving CBD also showed improvement that did not reach statistical significance in cognitive performance and overall functioning.
CBD was well tolerated, and adverse event rates were similar between the CBD and placebo groups.
Anxiety Disorder
- People suffering from primary and/or secondary anxiety disorders may benefit from phytocannabinoid treatment. CBD, through its multimodal effect, which includes increased levels of anandamide and 5HT-1A agonism, has been shown to be effective as an anxiolytic. Most of the clinical research has focused on its application to subjects suffering from social anxiety disorder or anxiety disorders associated to chronic pain, Parkinson's disease, and epilepsy.
- An additional benefit of CBD is that, by reducing anxiety levels, it may improve sleep patterns and optimize quality of life. It is important to remember that THC could be used in this population when combined with CBD in a 1:1 ratio, but THC-rich products are not recommended as they may be ansiogenic.
CLINICAL EVIDENCE
Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test. Brazilian Journal of Psychiatry. 2019. Ila M. Linares, Antonio W. Zuardi, Luis C. Pereira, Regina H. Queiroz, Raphael Mechoulam, Francisco S. Guimaraes Jose A. Crippa.
The aim of this study was to compare the acute effects of different doses of CBD and placebo in healthy volunteers who performed a simulated public speaking test (SPST), a well-documented test as an anxiety-inducing method. In this study, a total of 57 healthy male subjects were assigned to receive oral, dissolved in oil, or placebo CBD in a double-blind procedure. During SPST, subjective ratings were made on the visual analogue scale (VAMS) and physiological ratings. Measurements (systolic and diastolic blood pressure, heart rate) were obtained at six different points. Results: Compared with placebo, CBD pre-treatment significantly reduced anxiety during speech.
Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life. Frontiers in Pharmacology. 2017. Antonio W. Zuardi, Natália P. Rodrigues, Angélica L. Silva, Sandra A. Bernardo1, Jaime E. C. Hallak, Francisco S. Guimarães and José A. S. Crippa.
The purpose of this study was to investigate whether the anxiolytic effect of cannabidiol (CBD) in humans follows the same pattern of an inverted U-shaped dose-effect curve observed in many animal studies. Sixty healthy male and female subjects aged 18-35 years were randomly assigned to five groups receiving placebo, clonazepam, and CBD in oil. The subjects were tested in a real-life public speaking test (RPSS) where each subject had to speak in front of a group of the remaining participants. Each subject scored on a visual analogue mood scale and their blood pressure and heart rate were recorded. The results confirmed that acute CBD administration has anxiolytic effects induced by a dose-dependent inverted U-shaped curve.
Behavioural symptoms of dementia
- People with dementia generally present behavioural alterations (aggressiveness, hostility, ranting, aberrant behaviour, etc.) which are difficult to manage, require polymedication and are associated with a greater risk of overloading caretakers.
- The use of phytocannabinoids in this population has been associated with a reduction of such symptoms with a good margin of safety and tolerance. Although more studies are needed to strengthen the evidence in this field, the use of low-dose, non-psychoactive THC appears to be effective due to the sedative, appetite-stimulant and hypnotic effects, which are desirable in the context ofbehavioral alterations associated to neurodegenerative diseases.
- There are currently very few studies with CBD for this population, however, preparations with THC and CBD in 1:1 ratio appear to be a promising therapeutic option.
CLINICAL EVIDENCE
SSafety and Efficacy of Medical Cannabis Oil for Behavioral and Psychological
Symptoms of Dementia: An-Open Label, Add-On, Pilot Study. Journal of Alzheimer’s Disease 51 (2016). Assaf Shelef, Yoram Barak, Uri Berger, Diana Paleacu, Shelly Tadger, Igor Plopsky and Yehuda Baruch
Tetrahydrocannabinol (THC) is a potential treatment for the management of the behavioural symptoms of Alzheimer's disease (AD).
The aim of the study was to measure the efficacy and safety of THC-rich medical cannabis oil as an adjunct to pharmacotherapy, in relieving the behavioural and psychological symptoms of dementia. Eleven patients with AD were recruited for a 4-week prospective open-label trial. The patients received oral cannabis oil twice a day at 8:00 a.m. and 8:00 p.m. for 4 weeks. A significant reduction in the Clinical Global Impression improvement scale (CGI) severity score and the Neuropsychiatric Inventory (NPI) score was recorded. The NPI domains of significant decrease were: delusions, agitation/aggression, irritability, apathy, sleep and caregiver distress. Only 3 of the 11 patients reported minor adverse events. Adding THC-rich cannabis oil at a dose of 2.5 mg every 12 hours, orally, to the pharmacotherapy of patients with AD and behavioural symptoms is a safe and promising treatment option.
Post-Traumatic Stress Disorder
- Post-traumatic stress disorder (PTSD) is an anxiety disorder caused by very stressful, frightening or distressing events. Approximately 30% of this population is refractory to conventional treatment and experiences symptoms that deteriorate their quality of life. The role of the endocannabinoid system in processing traumatic experiences has revealed why the use of cannabis has become popular in populations exposed to traumatic situations (e.g. war veterans).
- Treatment with phytocannabinoids in people with PTSD has been proven effective at reducing symptoms of re-experimentation, avoidance, and hyperarousal. A very interesting finding has been the decrease in the frequency of nightmares and improvement in sleep quality with the use of THC. Further, CBD may help to reduce anxious symptoms and autonomic activation. However, medical cannabis should always be administered in conjunction with the patient's baseline treatment.
CLINICAL EVIDENCE
Preliminary, Open-Label, Pilot Study of Add-On Oral D9-Tetrahydrocannabinol in Chronic Post-Traumatic Stress Disorder. Clinical Drug Investigation. 2014. Pablo Roitman, Raphael Mechoulam, Rena Cooper-Kazaz, Arieh Shalev
Many patients with Post-Traumatic Stress Disorder (PTSD) achieve partial remission with current treatments. Patients with PTSD without symptomatic remission show high rates of substance abuse. Medical cannabis is often used as an adjunct therapy for treatment resistant PTSD. This open study assesses the tolerance and safety of orally absorbable D9-tetrahydrocannabinol (THC) for chronic PTSD. Ten outpatients with chronic PTSD, on stable medication, received D9-THC twice daily as an adjunctive treatment. There were mild adverse effects in three patients, none of which led to discontinuation of treatment. The intervention caused a statistically significant improvement in overall symptom severity, sleep quality, nightmare frequency and hyperarousal symptoms of PTSD.
Insomnia
Sleep disorders are very common in the general population, affecting about one in five people. The endocannabinoid system plays a key role in regulating neurovegetative functions such as sleep and appetite. Multiple studies have revealed the benefits of CBD and THC for people who suffer from insomnia associated with medical conditions such as chronic pain. Benefits have also been shown for people with anxiety disorders and associated insomnia.
CLINICAL EVIDENCE
Cannabidiol in Anxiety and Sleep: A Large Case Series
The aim of the study was to determine whether CBD helps improve sleep and/or anxiety in a clinical population. It is a large retrospective case series in a psychiatric clinic that evaluated the application of CBD (50 - 75 mg/day) for anxiety and sleep problems as an adjunct to usual treatment.
The final sample consisted of 72 adults who presented with anxiety (n = 47) or lack of sleep (n = 25). Anxiety scores decreased during the first month in 57 patients (79.2%) and remained decreased throughout the duration of the study. Sleep scores improved during the first month in 48 patients (66.7%) but fluctuated over time.
Cannabidiol (50 - 75 mg/day) may be beneficial for anxiety disorders. More controlled clinical studies are needed.
Effect of D-9-Tetrahydrocannabinol and Cannabidiolon Nocturnal Sleep and Early-Morning Behavior in Young Adults
This study measured the effects of cannabis extracts on night-time sleep, morning performance, memory, and drowsiness. Eight healthy volunteers participated (4 men, 4 women; 21-34 years old). The 4 treatments were placebo, 15 mg D-9-tetrahydrocannabinol
(THC), 5 mg THC combined with 5 mg cannabidiol (CBD), and 15 mg THC combined with 15 mg CBD.
Phytocannabinoids were administered oromucosally within 30 minutes from 10 p.m. Electroencephalograms were recorded during the sleep period (11 p.m. to 7 a.m.) performance, sleep latency, and subjective assessments of sleepiness and mood, which were measured from 8:30 a.m. (10 hours after drug administration). There was no change with 15 mg THC in night-time sleep. With concomitant administration of the balanced product (5 mg THC and 5 mg CBD to 15 mg THC and 15 mg CBD), there was a decrease in stage 3 of sleep, and with the combination of higher doses wakefulness increased. The next day, with 15 mg THC, memory was affected, sleep latency was reduced, and subjects reported increased sleepiness and changes in mood. With the lower dose combination, the reaction time was faster in the digit recovery task, and with the higher dose combination, the subjects reported increased drowsiness and mood changes. 15 milligrams of THC appear to be sedative, while 15 mg of CBD appears to have
- Chronic Pain
Chronic Pain
The International Association for the Study of Pain (IASP) defines chronic pain as a persistent or recurrent pain lasting more than three months, thus stablishing a highly-variable prevalence, between 8.7% and 64.4%, with an overall prevalence of 31%, affecting mainly female population.
Conventional treatment of chronic pain includes a multimodal analgesic regime that seeks to control or decrease the intensity of the pain. However, in some cases this conventional treatment does not achieve the desired therapeutic effects or may present untolerable side effects. In these cases, alternative therapeutic options may safely complement multimodal therapies for pain management. Current evidence supports the use of medical cannabis as a complementary therapeutic tool in certain cases of chronic pain.
Systematic reviews investigating treatment options for chronic pain and its symptoms have shown that cannabinoids are effective at controlling nociception, particularly for chronic neuropathic pain. Although there are several presentations and routes of administration, most studies have been conducted with inhaled THC.
Among the key systematic reviews documenting the effectiveness of cannabinoids for pain symptoms, a recent report by the US National Academy of Sciences, Engineering and Medicine found substantial and conclusive evidence for the efficacy of cannabinoids in addressing chronic pain in adults.11
- The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research Washington (DC): National Academies Press (US); 2017
CLINICAL EVIDENCE
Open-Label, Add-on Study of Tetrahydrocannabinol for Chronic Nonmalignant Pain.
Haroutiunian S, Rosen G, Shouval R, Davidson E. Open-label, add-on study of tetrahydrocannabinol for chronic nonmalignant pain. J Pain Palliat Care Pharmacother. 2008;22(3):213-217. doi:10.1080/15360280802251215
In this study, the safety and efficacy of the oral administration of Δ -9-tetrahydrocannabinol (THC) was evaluated in 13 patients with chronic non-oncological pain refractory to conventional therapy. The effect of the treatment was assessed through a health-related quality of life (HRQoL) questionnaire. Thirty-eight percent of patients reported a significant reduction in pain intensity.
53% experienced no adverse events, 2 of the patients who experienced adverse effects discontinued treatment.
The Effectiveness of Cannabinoids in the Management of Chronic Nonmalignant Neuropathic Pain A Systematic Review.
Boychuk DG, Goddard G, Mauro G, Orellana MF. The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: a systematic review. J Oral Facial Pain Headache. 2015;29(1):7-14. doi:10.11607/ofph.1274
This article is a systematic review assessing the effectiveness of cannabis extracts and cannabinoids in the treatment of chronic non-oncological neuropathic pain.
Twenty-four studies with patients presenting with chronic non-oncological neuropathic pain were reviewed, 11 studies were excluded. The 13 included studies were rated using the Jadad Scale for measuring bias in pain research, highly rated with a mean score of 4.9/5. Of these studies, 10 examined phytocannabinoids, 4 included smoked cannabis, 5 included cannabinoid-based extracts and 1 study was conducted with vaporized cannabinoids.
There is evidence of effective analgesia in chronic non-oncological neuropathic pain conditions. Including an improvement in sleep quality, appetite, nausea, and anxiety.
Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data.
Andreae MH, Carter GM, Shaparin N, et al. Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data. J Pain. 2015;16(12):1221-1232. doi: 10.1016/j.jpain.2015.07.009
This meta-analysis identifies that inhaled cannabis produces short-term benefits of at least 30% in reducing chronic neuropathic pain. A significant improvement was found at the individual patient level, with a number needed to treat (NNT) of approximately 5.6 for a short-term reduction in chronic neuropathic pain.
Efficacy of Cannabis-Based Medicines for Pain Management: A Systematic Review and Meta- Analysis of Randomized Controlled Trials. Aviram J, Samuelly-Leichtag G. In Response: Aviram J et al The Perils of Overestimating the Efficacy of Cannabis-Based Medicines for Chronic Pain Management. Pain Physician. 2018;21(1): E81-E83.
This systematic review of the literature suggests that cannabis products (CBM) have been shown to be effective in reducing chronic pain primarily for patients with chronic neuropathic pain. 43 Controlled Clinical Trials (CCTs) (a total of 2,437 patients) were included in this review, of which 24 CCTs (a total of 1,334 patients) were eligible for meta-analysis. This analysis showed moderate evidence of clinically significant improvement with decreased pain intensity (2 points or more of 30% or 50% or more), especially for inhalation compared to placebo.
Cannabis-based medicines for chronic neuropathic pain in adults (Review)
Mücke M, Carter C, Cuhls H, Prüß M, Radbruch L, Häuser W. Cannabinoide in der palliativen Versorgung : Systematische Übersicht und Metaanalyse der Wirksamkeit, Verträglichkeit und Sicherheit [Cannabinoids in palliative care: Systematic review and meta-analysis of efficacy, tolerability and safety]. Schmerz. 2016;30(1):25-36. doi:10.1007/s00482-015-0085-2
This Cochrane review summarizes the current evidence on the use of cannabis products for chronic neuropathic pain in adults, and in particular their efficacy, tolerability and safety compared to placebo or conventional medicines. Ten studies compared an oromucosal extract with a combination of naturally occurring tetrahydrocannabinol (THC) and cannabidiol (CBD) versus placebo. Two studies compared dried THC-rich cannabis flower versus placebo. Two studies compared a synthetic analogue of THC (Nabilone) versus placebo and an analgesic (dihydrocodeine), respectively.
All cannabinoid products (at any dose) combined were superior to placebo for significant (50% and above) and moderate (30% and above) pain relief, for overall improvement and reduction in mean pain intensity, sleep problems and emotional symptoms.
- Oncological Pain
- Chemotherapy-induced Nausea and Vomiting (CINV)
- Anorexia (loss of appetite)
- Insomnia
- Anxiety and Depression
Oncological Pain
- Most controlled clinical trials investigating the efficacy of cannabis to control pain in cancer were conducted using oral cannabis extracts containing both THC and CBD in similar proportion, and reported positive therapeutic effects for the control of pain and other associated symptoms in this clinical population. However, recent studies have shown no obvious analgesic effect elicited by the co-administration of nabiximols and opioids in patients with cancer pain.
CLINICAL EVIDENCE
Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study of the Efficacy, Safety, and Tolerability of THC:CBD Extract and THC Extract in Patients with Intractable Cancer-Related Pain. J Pain Symptom Manage. 2010;39(2):167–79.
This is a double-blind, randomised, controlled study, 177 patients with opioid-refractory cancer pain (scores on the verbal numeric scale ≥ 4), over 2 weeks. The patients were randomized to THC extract: Balanced CBD (n = 60), THC-rich extract (n = 58) or placebo (n = 59). The study shows that an extract with similar THC and CBD content in low (10.8mg THC and 10mg CBD) and medium (21.6mg THC and 20mg CBD) doses was effective in relieving opioid-refractory cancer pain. Low tolerability with high doses (> 30mg THC) was reported.
Boland EG, Bennett MI, Allgar V, Boland JW. Cannabinoids for adult cancer-related pain: systematic review and meta-analysis. BMJ Support Palliat Care. 2020;10(1):14–24.
This systematic review of the literature and meta-analyses of controlled clinical trials showed that there was no statistically significant difference for reduction in cancer pain intensity in patients receiving cannabinoids versus placebo. The cannabinoids used in the studies included in this systematic review and meta-analysis were nabiximoles (oromucosal spray containing natural extract of Cannabis sativa with similar amounts of THC/CBD). The group receiving nabiximoles had a higher risk of developing side effects, mainly drowsiness and dizziness.
Chemotherapy-induced Nausea and Vomiting (CINV)
- Most studies support the use of nabilone (synthetic analogue of THC) and dronabinol (synthetic THC) as adjuvants in the management of chemotherapy-induced nausea and vomiting (CINV). Preclinical evidence has demonstrated that antiemetic effects of cannabis require the activation of CB1 receptors by THC and that cannabinoids are effective at suppressing the anticipatory nausea in animals.
CLINICAL EVIDENCE
Machado Rocha FC, Stéfano SC, De Cássia Haiek R, Rosa Oliveira LMQ, Da Silveira DX. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J Cancer Care (Engl). 2008 Sep;17(5):431–43.
This systematic review of the literature assessed the antiemetic effect of cannabinoids in cancer patients undergoing chemotherapy. Thirty controlled clinical trials were included in the systematic review, with a total of 1719 patients suffering from different types of cancer, and 13 controlled clinical trials in the meta-analysis. Most of the studies (except three that used chlorpromazine, domperidone and alizapride) compared cannabinoids versus prochlorperazine (neuroleptic). Dronabinol (synthetic THC) showed an antiemetic effect superior to neuroleptics in cancer patients undergoing chemotherapy. Nabilone and levonantradol did not show a statistically significant superior efficacy to conventional antiemetics, but there was a significant clinical difference towards intervention with these synthetic cannabinoids. Adverse effects were more intense and frequent in the group of patients receiving cannabinoids. Patients on chemotherapy showed a greater preference for cannabinoids to control their nausea and vomiting.
Meiri E, Jhangiani H, Vredenburgh JJ, Barbato LM, Carter FJ, Yang H-M, et al. Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin. 2007 Mar;23(3):533–43.
This controlled clinical trial compared the efficacy and tolerability of dronabinol, ondansetron, or the combination of these drugs, for the management of nausea and vomiting secondary to chemotherapy. The study was conducted over five days, 61 patients were analysed and doses of up to 20 mg of dronabinol and 16 mg of ondansetron were reached. Total response to treatment was defined as nausea intensity less than 5 mm on a visual analogue scale, absence of vomiting and non-use of rescue antiemetics. The overall response was similar in all three groups: dronabinol (54%), ondansetron (58%), and combination therapy (47%) versus placebo (20%). Nausea intensity was lower in the group receiving dronabinol. Although limited by sample size, dronabinol and ondansetron showed similar effectiveness in controlling nausea and vomiting secondary to chemotherapy and were well tolerated by patients.
Anorexia (loss of appetite)
- Activation of CB1 receptors in the lateral portion of the hypothalamus and the limbic system appear to be associated with the control of food intake, seemly by regulating motivational and rewarding properties of eating. Most studies conducted in anorexic patients using dronabinol and/or THC-dominant products have shown an increase in appetite without significant impact on weight or other nutritional variables. In addition, THC appears to have an impact on food palatability and the enjoyment of eating, although the evidence is still limited to support its use to stimulate food appetite in cancer patients.
CLINICAL EVIDENCE
Bar-Sela G, Zalman D, Semenysty V, et al. The Effects of Dosage-Controlled Cannabis Capsules on Cancer-Related Cachexia and Anorexia Syndrome in Advanced Cancer Patients: Pilot Study. Integr Cancer Ther. 2019; 18: 1534735419881498
This pilot study in Israel included 11 patients with cancer-associated anorexia cachexia syndrome who received controlled doses of cannabinoids in capsule form that were administered orally. The doses administered were 10 mg THC every 12 hours (CBD 0.5 mg in each capsule). Patients reported less loss of appetite in the cannabinoid group versus the control group, as well as an improvement in other symptoms such as pain, fatigue, and mood. The treatment was well tolerated. Clinical studies with larger sample sizes are required to confirm these results.
Insomnia
- The evidence for the use of cannabinoids for sleep disorders in patients with advanced cancer is limited. However, based on previous literature on the effects of cannabinoids in patients with impaired sleep quality in other clinical settings, the medical literature suggests that the use of THC-rich products may improve sleep patterns. In some cases, CBD may also ameliorate the quality of sleep through its anxiolytic effect although in some patients CBD has paradoxically produced insomnia.
Anxiety and Depression
- In cancer patients suffering from anxiety, the medical literature supports the use of CBD-rich products because of their recognized anxiolytic effect. In these cases it is important to avoid THC-rich products, as some psychiatric conditions can be exacerbated (in the case of patients with psychosis, schizophrenia, bipolar disorder, etc.) and the intensity of the anxiety may well be worsened. In the case of patients without a history of mental illness and experienced with cannabis use, a balanced product with similar amounts of THC and CBD could be indicated.
When depression occurs as a symptom associated with cancer and/or the terminal condition, low-dose THC may improve the mood in these patients. However, increasing the doses of THC may worsen the depression and a paradoxical effect have been observed in studies using nabiximols at high doses. Therefore, THC-rich or balanced with CBD on a 1:1 ratio could be recommended, always paying attention to THC doses and starting with the lowest possible dose.
CLINICAL EVIDENCE
Cyr C, Arboleda MF, Aggarwal SK, Balneaves LG, Daeninck P, Néron A, et al. Cannabis in palliative care: current challenges and practical recommendations. Ann Palliat Med. 2018 Oct;7(4):463–77.
This review article discusses the challenges faced by doctors in prescribing cannabinoids and provides practical recommendations for the use of medical cannabis in patients with advanced disease. In the case of patients with insomnia, experts recommend the use of THC-rich products. If patients suffer from insomnia, it is suggested that products where THC is predominant should be administered by the inhaled route, as the onset of action is rapid (3-10 minutes). If patients have difficulty in sleeping at night, experts suggest oral THC-rich products, as the duration of action is long (8-12 hours or more). In the case of anxiety, it is suggested to use products rich in CBD mainly by mouth, for symptoms that are persistent. In the event of panic attacks or anxiety crises, it is suggested that products rich in CBD be administered by inhalation. Finally, in patients with symptoms of depression associated with cancer, it is suggested that low doses of THC be administered orally. High doses may have a paradoxical effect and worsen the depression.
Schleider LB, Mechoulam R, Lederman V, et al. Prospective Analysis of Safety and Efficacy of Medical Cannabis in Large Unselected Population of Patients With Cancer. Eur J Intern Med. 2018; 49: 37-43.
This prospective, observational study conducted in Israel shows a cohort of 2970 patients with different types of cancer who were given cannabinoids between 2015 and 2017. Seventy-eight percent of the patients were treated with medical cannabis for sleep disorders, 77.7% for moderate pain, 72.7% for fatigue management, 64.6% for nausea management and 48.9% for anorexia. After 6 months of treatment with cannabinoids, 95.9% reported improvement in the intensity of their symptoms and 69.5% reported a positive impact on their health-related quality of life. The symptoms that showed the greatest response to cannabinoid treatment were: nausea and vomiting, insomnia, anxiety and depression. The authors concluded that medical cannabis was well tolerated by cancer patients and is an effective and safe option that can help control different symptoms in advanced disease.
Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015;313(24):2456–73
This systematic review of the literature and meta-analysis, which included 79 controlled clinical trials (6462 patients), evaluated the benefits and adverse effects of cannabinoids in different clinical settings. In the case of insomnia, there are no studies that have specifically included cancer patients. However, the clinical trials considered in this systematic review and meta-analysis report an improvement in the pattern and quality of sleep. These studies included insomnia as a symptom associated with pain, finding an optimal therapeutic effect in this population.
On the other hand, depression secondary to cancer has not been studied. It is necessary to identify that high doses of nabiximoles have shown negative effects on depression.
In terms of anxiety, CBD showed significant benefits in patients with social anxiety disorder. Studies specifically of cancer patients were not included. Additional data on anxiety outcomes were identified in patients with chronic pain.
- SUBSTANCE USE DISORDERS (AS A HARM REDUCTION STRATEGY)
- Tobacco Consumption
Substance use disorders
A growing body of academic research arising from jurisdictions in which consumers have been granted access to a standardized, government-regulated source of medical cannabis, such as Canada or several states of the US, suggests that use of medical cannabis can result in a reduction in the use of and subsequent harms associated with opioids, alcohol, tobacco, and other substances.
CLINICAL EVIDENCE
Lucas, P. et al. Substituting cannabis for prescription drugs, alcohol and other substances among medical cannabis patients: The impact of contextual factors. Drug Alcohol Rev. 35, 326–333 (2016).
The present study examines the use of cannabis as a substitute for alcohol, illicit substances and prescription drugs among 473 adults who use cannabis for therapeutic purposes. The Cannabis Access for Medical Purposes Survey is a 414-question cross-sectional survey that was available to Canadian medical cannabis patients online and by hard copy in 2011 and 2012 to gather information on patient demographics, medical conditions and symptoms, patterns of medical cannabis use, cannabis substitution and barriers to access to medical cannabis. Substituting cannabis for one or more of alcohol, illicit drugs or prescription drugs was reported by 87% (n=410) of respondents, with 80.3% reporting substitution for prescription drugs, 51.7% for alcohol, and 32.6% for illicit substances. The finding that cannabis was substituted for all three classes of substances suggests that the medical use of cannabis may play a harm reduction role in the context of use of these substances, and may have implications for abstinence-based substance use treatment approaches. Further research should seek to differentiate between biomedical substitution for prescription pharmaceuticals and psychoactive drug substitution, and to elucidate the mechanisms behind both.
Reiman, A., Welty, M. & Solomon, P. Cannabis as a Substitute for Opioid-Based Pain Medication: Patient Self-Report. Cannabis cannabinoid Res. 2, 160–166 (2017).
The current study examined the use of cannabis as a substitute for opioid-based pain medication by collecting survey data from 2897 medical cannabis patients. Thirty-four percent of the sample reported using opioid-based pain medication in the past 6 months. Respondents overwhelmingly reported that cannabis provided relief on par with their other medications, but without the unwanted side effects. Ninety-seven percent of the sample "strongly agreed/agreed" that they are able to decrease the amount of opiates they consume when they also use cannabis, and 81% "strongly agreed/agreed" that taking cannabis by itself was more effective at treating their condition than taking cannabis with opioids. Results were similar for those using cannabis with nonopioid-based pain medications.
Lucas, P., Baron, E. P. & Jikomes, N. Medical cannabis patterns of use and substitution for opioids & other pharmaceutical drugs, alcohol, tobacco, and illicit substances; Results from a cross-sectional survey of authorized patients. Harm Reduction Journal vol. 16 (2019).
A 239-question cross-sectional survey was sent out via email in January 2017 to gather comprehensive information on cannabis use from Canadian medical cannabis patients registered with a federally authorized licensed cannabis producer, resulting in 2032 complete surveys. Participants were 62.6% male (n = 1271) and 91% Caucasian (n = 1839). The mean age was 40 years old, and pain and mental health conditions accounted for 83.7% of all respondents (n = 1700). Then, 74.6% of respondents reported daily cannabis use (n = 1515) and mean amount used per day was 1.5 g. The most cited substitution was for prescription drugs (69.1%, n = 953), followed by alcohol (44.5%, n = 515), tobacco (31.1%, n = 406), and illicit substances (26.6%, n = 136). Opioid medications accounted for 35.3% of all prescription drug substitution (n = 610), followed by antidepressants (21.5%, n = 371). Of the 610 mentions of specific opioid medications, patients report total cessation of use of 59.3% (n = 362). The findings provide a granular view of patient patterns of medical cannabis use, and the subsequent self-reported impacts on the use of opioids, alcohol, and other substances.
Morgan, C. J. A., Das, R. K., Joye, A., Curran, H. V. & Kamboj, S. K. Cannabidiol reduces cigarette consumption in tobacco smokers: Preliminary findings. Addict. Behav. 38, 2433–2436 (2013).
A pilot, randomised double blind placebo-controlled study set out to assess the impact of the ad-hoc use of cannabidiol (CBD) in smokers who wished to stop smoking. 24 smokers were randomised to receive an inhaler of CBD (n. =. 12) or placebo (n. =. 12) for one week, they were instructed to use the inhaler when they felt the urge to smoke. Over the treatment week, placebo treated smokers showed no differences in number of cigarettes smoked. In contrast, those treated with CBD significantly reduced the number of cigarettes smoked by ~. 40% during treatment. Results also indicated some maintenance of this effect at follow-up. These preliminary data, combined with the strong preclinical rationale for use of this compound, suggest CBD to be a potential treatment for nicotine addiction that warrants further exploration
Tobacco Consumption
Pharmacological manipulation of the endocannabinoid system is being investigated for the treatment of addictive behaviors, tobacco smoking in particular, where the role of the endocannabinoid system in nicotine addiction is being increasingly acknowledged. Preliminary clinical evidence seems to indicate that inhaled CBD could be an effective strategy to reduce nicotine craving and addiction and a useful therapeutic tool to help with tobacco cessation.
CLINICAL EVIDENCE
Cannabidiol reduces cigarette consumption in tobacco smokers: preliminary findings.
A pilot, randomised double blind placebo-controlled study set out to assess the impact of the ad-hoc use of cannabidiol (CBD) in smokers who wished to stop smoking. 24 smokers were randomised to receive an inhaler of CBD (n. =. 12) or placebo (n. =. 12) for one week, they were instructed to use the inhaler when they felt the urge to smoke. Over the treatment week, placebo treated smokers showed no differences in number of cigarettes smoked. In contrast, those treated with CBD significantly reduced the number of cigarettes smoked by ~. 40% during treatment. Results also indicated some maintenance of this effect at follow-up. These preliminary data, combined with the strong preclinical rationale for use of this compound, suggest CBD to be a potential treatment for nicotine addiction that warrants further exploration
- Gastrointestinal diseases
- Ulcerative colitis
- Crohn’s disease
Gastrointestinal diseases
- A significant body of preclinical evidence suggest that the endocannabinoid system serves a protective role on the gastrointestinal mucosa. For example, activation of CB1 receptor is protective against NSAID-induced gastric irritation. Pharmacological modulation of the endogenous cannabinoid system could provide new therapeutics for the treatment of several gastrointestinal diseases, including nausea and vomiting, gastric ulcers, irritable bowel syndrome, Crohn's disease, secretory diarrhea, paralytic ileus and gastroesophageal reflux disease.
CLINICAL EVIDENCE
Di Carlo, G. & Izzo, A. A. Cannabinoids for gastrointestinal diseases: Potential therapeutic applications. Expert Opinion on Investigational Drugs vol. 12 39–49 (2003).
Δ9-Tetrahydrocannabinol (the active ingredient of marijuana), as well as endogenous and synthetic cannabinoids, exert many biological functions by activating two types of cannabinoid receptors, CB1 and CB2 receptors. CB1 receptors have been detected on enteric nerves, and pharmacological effects of their activation include gastroprotection, reduction of gastric and intestinal motility and reduction of intestinal secretion. The digestive tract also contains endogenous cannabinoids (i.e., the endocannabinoids anandamide and 2-aracidonylglycerol) and mechanisms for endocannabinoid inactivation (i.e., endocannabinoids uptake and enzymatic degradation). Cannabinoid receptors, endocannabinoids and the proteins involved in endocannabinoids inactivation are collectively referred as the 'endogenous cannabinoid system'. A pharmacological modulation of the endogenous cannabinoid system could provide new therapeutics for the treatment of several gastrointestinal diseases, including nausea and vomiting, gastric ulcers, irritable bowel syndrome, Crohn's disease, secretory diarrhea, paralytic ileus and gastroesophageal reflux disease. Some cannabinoids are already in use clinically, for example, nabilone and Δ9-tetrahydrocannabinol are used as antiemetics.
Ulcerative colitis
- Preclinical evidence suggests that activation of CB1 receptors in the colon may exert a therapeutic effect on ulcerative colitis by attenuating inflammation. There is a higher prevalence of cannabis use among patients with IBD compared to the general population Cannabis may relieve symptoms of ulcerative colitis such as abdominal pain, reduced appetite, and diarrhea. However, it is not known if these potential benefits are related to centrally acting psychotropic effects or to anti-inflammatory. In humans, there is evidence that CBD-rich botanical extract may be beneficial for symptomatic treatment of ulcerative colitis
CLINICAL EVIDENCE
Kafil, T. S., Nguyen, T. M., Macdonald, J. K. & Chande, N. Cannabis for the treatment of ulcerative colitis. Cochrane Database Syst. Rev. 2018, (2018).
This is a protocol for a Cochrane Review (Intervention). The objective is to assess the benefits and harms of cannabis for the treatment of patients with ulcerative colitis.
Irving, P. M. et al. A Randomized, Double-blind, Placebo-controlled, Parallel-group, Pilot Study of Cannabidiol-rich Botanical Extract in the Symptomatic Treatment of Ulcerative Colitis. Inflamm. Bowel Dis. 24, 714–724 (2018).
This proof-of-concept study assessed efficacy, safety, and tolerability of CBD-rich botanical extract in ulcerative colitis (UC) patients. Patients were less tolerant of CBD-rich botanical extract compared with placebo, taking on average one-third fewer capsules, and having more compliance-related protocol deviations (principally insufficient exposure), prompting identification of a per protocol (PP) analysis set. The primary endpoint was negative; end of treatment remission rate was similar for CBD-rich botanical extract (28%) and placebo (26%). However, PP analysis of total and partial Mayo scores favoured CBD-rich botanical extract (P = 0.068 and P = 0.038, respectively). Additionally, PP analyses of the more subjective physician's global assessment of illness severity, subject global impression of change, and patient-reported quality-of-life outcomes were improved for patients taking CBD-rich botanical extract (P = 0.069, P = 0.003, and P = 0.065, respectively). Adverse events (AEs) were predominantly mild/moderate with many in the CBD-rich botanical extract group potentially attributable to the ∆9-tetrahydrocannabinol content. A greater proportion of gastrointestinal-related AEs, indicative of UC worsening, was seen on placebo.
Crohn’s disease
- Cannabis and derived products have been reported to produce beneficial effects for patients with inflammatory bowel diseases, but this has only been investigated in a few small controlled trials. Results seem to indicate that THC-rich cannabis produced significant clinical, steroid-free benefits to patients with active Crohn’s disease, compared with placebo, without side effects.
- However, the effects of cannabis and cannabis products on Crohn’s disease remain uncertain. Thus, no firm conclusions regarding the efficacy and safety of cannabis and cannabis products in adults with active Crohn’s disease can be drawn so far. Further studies with larger numbers of participants are required to assess the potential benefits and harms of cannabis in Crohn’s disease.
CLINICAL EVIDENCE
Kafil, T. S., Nguyen, T. M., Macdonald, J. K. & Chande, N. Cannabis for the treatment of Crohn’s disease. Cochrane Database of Systematic Reviews vol. 2018 (2018).
Crohn’s disease (CD) is a chronic immune-mediated condition of transmural inflammation in the gastrointestinal tract, associated with significant morbidity and decreased quality of life. The endocannabinoid system provides a potential therapeutic target for cannabis and cannabinoids and animal models have shown benefit in decreasing inflammation. However, there is also evidence to suggest transient adverse events such as weakness, dizziness and diarrhea, and an increased risk of surgery in people with CD who use cannabis. The objectives were to assess the efficacy and safety of cannabis and cannabinoids for induction and maintenance of remission in people with CD
Naftali, T. et al. Cannabis induces a clinical response in patients with crohn’s disease: A prospective placebo-controlled study. Clin. Gastroenterol. Hepatol. 11, (2013).
A prospective trial aimed to determine whether cannabis can induce remission in patients with Crohn's disease. We studied 21 patients (mean age, 40 ± 14 y; 13 men) with Crohn's Disease Activity Index (CDAI) scores greater than 200 who did not respond to therapy with steroids, immunomodulators, or anti-tumor necrosis factor-α agents. Patients were assigned randomly to groups given cannabis, twice daily, in the form of cigarettes containing 115 mg of δ9-tetrahydrocannabinol (THC) or placebo containing cannabis flowers from which the THC had been extracted. Disease activity and laboratory tests were assessed during 8 weeks of treatment and 2 weeks thereafter. Results: Complete remission (CDAI score, <150) was achieved by 5 of 11 subjects in the cannabis group (45%) and 1 of 10 in the placebo group (10%; P= .43). A clinical response (decrease inCDAI score of >100) was observed in 10 of 11 subjects in the cannabis group (90%; from 330 ± 105 to 152 ± 109) and 4 of 10 in the placebo group (40%; from 373 ± 94 to 306 ± 143; P= 028). Three patients in the cannabis group were weaned from steroid dependency. Subjects receiving cannabis reported improved appetite and sleep, with no significant side effects. Although the primary end point of the study (induction of remission) was not achieved, a short course (8 weeks) of THC-rich cannabis produced significant clinical, steroid-free benefits to 10 of 11 patients with active Crohn's disease, compared with placebo, without side effects.
Naftali, T. et al. Low-Dose Cannabidiol Is Safe but Not Effective in the Treatment for Crohn’s Disease, a Randomized Controlled Trial. Dig. Dis. Sci. 62, 1615–1620 (2017).
A study assessing the effects of cannabidiol on Crohn’s disease in a randomized placebo-controlled trial. Twenty patients aged 18–75 years with a Crohn’s disease activity index (CDAI) >200 were randomized to receive oral (10 mg) CBD or placebo twice daily. Patients did not respond to standard treatment with steroids (11 patients), thiopurines (14), or TNF antagonists (11). Disease activity and laboratory parameters were assessed during 8 weeks of treatment and 2 weeks thereafter. Other medical treatment remained unchanged. Of 20 patients recruited 19 completed the study. Their mean age was 39 ± 15, and 11 were males. The average CDAI before cannabidiol consumption was 337 ± 108 and 308 ± 96 (p = NS) in the CBD and placebo groups, respectively. After 8 weeks of treatment, the index was 220 ± 122 and 216 ± 121 in the CBD and placebo groups, respectively (p = NS). Hemoglobin, albumin, and kidney and liver function tests remained unchanged. No side effects were observed.